Many diseases of the skin have unique anatomic manifestations that have important implications for diagnosis, prognosis, and treatment. It is well known that site- specific development in the skin is shaped by reciprocal epithelial-mesenchymal interactions. Discovering the molecular mechanisms that govern this interaction is vital to our understanding of skin disease. The HOX genes are transcription factors that are regulated in an exquisite temporal and spatial manner to specify proper positional patterning of body structures including the skin. Our laboratory has discovered that a new class of pervasive genes, long noncoding RNAs (lincRNAs), in the HOX loci show striking site-specific expression in skin fibroblasts. One lncRNA located at the distal end of the HOXA locus, termed HOTTIP, is expressed in dermal fibroblasts from distal and posterior body sites. Depletion of this RNA leads to a suppression of expression of contiguous distal HOXA genes, suggesting a role for this ncRNA in distal dermal and epidermal patterning at least in part through transcriptional activation of the HOXA locus. HOTTIP also binds to WDR5, a component of the chromatin modifying complex Mixed- Lineage Leukemia-1 (MLL-1), suggesting it may demarcate domains of chromosomal remodeling via interactions with MLL-1. The goals of this proposal are aimed at: 1) understanding the molecular mechanisms of HOTTIP-mediated gene regulation and transcriptional activation, and 2) defining the functional role for HOTTIP and other WDR5-binding lncRNAs in differentiation and developmental patterning in vivo. The results will expand our knowledge of the role of lncRNAs in skin fibroblast function and positional identity with implications for understanding clinically relevant issues in dermatology such as wound regeneration and site-specific disease manifestations. This award will enable the principle investigator, a dermatology trained physician-scientist, to receive intensive training in skin biology research and develop his own independent research program. Stanford University is providing him full institutional support, extensive resources, and opportunity for collaborations with experts in the field. The department has a strong track-record in mentoring dermatology physician-scientists to independent positions. He will be trained in ethical conduct, experimental design, and laboratory management to transition him to a full-time academic tenure-track position in translational dermatology research where he will spend 90% of his time on research and 10% on clinical activities. PUBLIC HEALTH RELEVANCE: This proposal is focused on understanding at the molecular level how skin from different parts of the body develops unique anatomical features. Many diseases of the skin, such as psoriasis and scleroderma, have site-specific manifestations. Understanding the mechanism of why this occurs has important implications for designing the best treatment options.